One widely considered approach to identify susceptibility alleles is through linkage disequilibrium (LD) between these alleles and a universal set of relatively frequent SNPs distributed in all or most ethnic populations. This approach, however, may be unrealistic when variant alleles responsible for disease susceptibility are infrequent or are specific to a particular population. In such cases, identifying susceptibility alleles may require comprehensive sequence comparison between patients and controls. There is a paucity of techniques for high throughput scanning for unknown variations. Mismatch Repair Detection (MRD)'s potential for high throughput scanning can be used to comprehensively compare sequences between patients and controls. MRD has been described previously and it utilizes a bacterial mismatch repair system in vivo to detect sequence variants in human DNA samples. Many fragments can be introduced into a specific bacterial strain Mutation Sorter (MS) that is engineered to sort these fragments to two pools: those carrying variations and those that do not. The problem of DNA variation detection in then reduced to the problem of identification of the fragment content of the two pools, and that can be done using a microarray hybridization. In phase II of this grant we aim to apply MRD multiplex scanning ability to test about 1,000 candidate exons in hundreds of patients and controls to identify susceptibility alleles of a complex trait. In the long term, we see applying MRD on a whole genomic scale to scan all the exons of patients and controls to elucidate the genetic basis of complex disease.